JP7492781B2 - Crystalline forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride, methods for making such forms and pharmaceutical compositions thereof - Google Patents

Description

FIELD This disclosure relates to crystalline forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride, as well as compositions, processes for preparation and uses thereof.

FIELD OF THE DISCLOSURE [0002] As improved drug formulations exhibiting, for example, better bioavailability or better stability are continually sought, there is a continuing need for more fully characterized, new, polymorphic and derivative forms of drug molecules. Characterization of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride, as well as crystalline polymorphs and metabolites of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride, is described herein for this purpose.

SUMMARY OF THE DISCLOSURE The present disclosure includes a crystalline form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride characterized by a PXRD pattern shown in FIG. 1, FIG. 4, or FIG. 8. The crystalline form is further characterized by an FTIR spectrum shown in FIG. 5 or FIG. 9. The crystalline form is further characterized by a ¹ H-NMR spectrum shown in FIG. 6 or FIG. 10. The crystalline form is further characterized by a particle shape shown in FIG. 2, FIG. 3, FIG. 7, or FIG. 11. The crystalline form is further characterized by a particle size shown in FIG. 2, FIG. 3, FIG. 7, or FIG. 11. The crystalline form may have a plate-like habit. The crystalline form may also have a needle-like habit. The crystalline form may have a lath-like habit. Also included is a method for making the crystalline form using supercritical fluid (SCF) techniques. Further included are dosage forms comprising a therapeutically neuroprotective amount of the crystalline form. Further included are pharmaceutical compositions for the treatment of Alzheimer's disease comprising a therapeutically effective amount of the crystalline form. Further included are methods for treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of the crystalline form.

The present disclosure also includes crystalline Form I of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride characterized by the PXRD pattern shown in FIG. 1. The crystalline Form I is accordingly characterized by a particle shape as shown in FIG. 2. The crystalline Form I is also characterized by a particle shape as shown in FIG. 3. The crystalline Form I is also characterized by a particle size as shown in FIG. 2. The crystalline Form I is also characterized by a particle size as shown in FIG. 3. The crystalline Form I is also characterized by a plate-like crystal habit. Further included is a method for making crystalline Form I using supercritical fluid (SCF) techniques. Further included is a dosage form comprising a therapeutically neuroprotective amount of crystalline Form I. Further included is a pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of crystalline Form I. Also included is a method for treating Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of crystalline Form I.

The present disclosure also includes crystalline Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride characterized by the PXRD pattern shown in Figure 4. Crystalline Form II is also characterized by the FTIR spectrum shown in Figure 5. Crystalline Form II is also characterized by the ¹ H-NMR spectrum shown in Figure 6. Crystalline Form II is also characterized by the particle shape as shown in Figure 7. Crystalline Form II is also characterized by the particle size as shown in Figure 7. Crystalline Form II may also have a plate-like crystal habit. Further included is a method for making crystalline Form II using supercritical fluid (SCF) techniques. Further included is a dosage form comprising a therapeutically neuroprotective amount of crystalline Form II. Further included is a pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of crystalline Form II. Further included is a method for treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of crystalline Form II.

The present disclosure also includes crystalline Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride characterized by the PXRD pattern shown in Figure 8. Crystalline Form III is also characterized by the FTIR spectrum shown in Figure 9. Crystalline Form III is also characterized by the ¹ H-NMR spectrum shown in Figure 10. Crystalline Form III is also characterized by the particle shape as shown in Figure 11. Crystalline Form III is also characterized by the particle size as shown in Figure 11. Crystalline Form III may also have a lath-like crystal habit. Further included is a method for making crystalline Form III using supercritical fluid (SCF) techniques. Further included is a dosage form comprising a therapeutically neuroprotective amount of crystalline Form III. Further included is a pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of crystalline Form III. Further included is a method for treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of crystalline Form III.

The present disclosure also includes metabolite ANAVEX19-144, characterized by the PXRD pattern shown in FIG. 12. Metabolite ANAVEX19-144 is also characterized by DSC-TGA data shown in FIG. 13. Metabolite ANAVEX19-144 is also characterized by the FTIR spectrum shown in FIG. 14. Metabolite ANAVEX19-144 may also be characterized by particle shape as shown in FIG. 15. Metabolite ANAVEX19-144 may also be characterized by particle size as shown in FIG. Metabolite ANAVEX19-144 may also have a needle-like crystal habit. Further included are methods for making metabolite ANAVEX19-144 using supercritical fluid (SCF) techniques. Further included are dosage forms comprising a therapeutically neuroprotective amount of metabolite ANAVEX19-144. Further included is a pharmaceutical composition for the treatment of Alzheimer's disease, comprising a therapeutically effective amount of the metabolite ANAVEX19-144. Further included is a method for treating Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of the metabolite ANAVEX19-144.

The present disclosure also includes metabolite ANAVEX19-144, which is characterized by the PXRD pattern shown in Figure 17. Metabolite ANAVEX19-144 is also characterized by the DSC-TGA data shown in Figure 18. Metabolite ANAVEX19-144 may also be characterized by particle shape as shown in Figure 16. Metabolite ANAVEX19-144 may also be characterized by particle size as shown in Figure 16. Further included are methods for making metabolite ANAVEX19-144 using supercritical fluid (SCF) techniques. Further included are methods for making metabolite ANAVEX19-144 using supercritical fluid (SCF) techniques.
and a dosage form comprising a therapeutically neuroprotective amount of metabolite ANAVEX 19-144. Further included is a pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of metabolite ANAVEX 19-144. Further included is a method for treating Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of metabolite ANAVEX 19-144.

To describe the manner in which the advantages and features of the present disclosure may be obtained, reference will be made to embodiments thereof which are illustrated in the accompanying drawings. With the understanding that these drawings merely depict exemplary embodiments of the present disclosure and therefore should not be considered limiting of its scope, the principles herein will be described and explained with added specificity and detail through the use of the accompanying drawings.
The present invention provides, for example, the following items.
(Item 1)
A crystalline form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride characterized by the PXRD pattern shown in FIG. 1, FIG. 4, or FIG.
(Item 2)
Item 1. The crystalline form of item 1, further characterized by the FTIR spectrum shown in FIG. 5 or FIG.
(Item 3)
2. The crystalline form of claim 1, further characterized by the ¹ H-NMR spectrum shown in FIG. 6 or FIG.
(Item 4)
2. The crystalline form of claim 1, further characterized by the particle shape shown in FIG. 2, FIG. 3, FIG. 7 or FIG. 11.
(Item 5)
2. The crystalline form of claim 1, further characterized by the particle size as shown in FIG. 2, FIG. 3, FIG. 7 or FIG. 11.
(Item 6)
2. The crystalline form according to claim 1, wherein the crystal habit is plate-like.
(Item 7)
2. The crystalline form according to claim 1, wherein the crystal habit is needle-like.
(Item 8)
2. The crystalline form according to claim 1, wherein the crystal habit is lath-like.
(Item 9)
2. A method for making the crystalline form of claim 1, comprising using supercritical fluid (SCF) technology.
(Item 10)
2. A dosage form comprising a therapeutically neuroprotective amount of the crystalline form of claim 1.
(Item 11)
9. A pharmaceutical composition for the treatment of Alzheimer's disease, comprising a therapeutically effective amount of the crystalline form according to any one of items 1 to 8.
(Item 12)
9. A method for treating Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline form according to any one of items 1 to 8.
(Item 13)
Crystalline Form I of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride is characterized by the PXRD pattern shown in FIG.
(Item 14)
Item 14. Crystalline form I according to item 13, characterized by a particle shape as shown in FIG.
(Item 15)
Item 14. Crystalline form I according to item 13, characterized by a particle shape as shown in FIG.
(Item 16)
Item 14. Crystalline form I according to item 13, characterized by the particle size as shown in FIG.
(Item 17)
Item 14. Crystalline form I according to item 13, characterized by a particle size as shown in FIG.
(Item 18)
14. The crystalline form according to item 13, wherein the crystal habit is plate-like.
(Item 19)
19. A method for making the crystalline form according to any of items 13 to 18, comprising using supercritical fluid (SCF) technology.
(Item 20)
19. A dosage form comprising a therapeutically neuroprotective amount of the crystalline form of any of items 13 to 18.
(Item 21)
19. A pharmaceutical composition for the treatment of Alzheimer's disease, comprising a therapeutically effective amount of the crystalline form according to any one of items 13 to 18.
(Item 22)
19. A method for treating Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline form according to any of items 13 to 18.
(Item 23)
Crystalline Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride is characterized by the PXRD pattern shown in FIG.
(Item 24)
Crystalline Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride, characterized by the FTIR spectrum shown in FIG. 5. (Item 25)
Crystalline Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride characterized by the ¹ H-NMR spectrum shown in FIG.
(Item 26)
26. The crystalline form II according to any of items 23 to 25, characterized by a particle shape as shown in FIG.
(Item 27)
26. The crystalline form II according to any of items 23 to 25, characterized by a particle size as shown in FIG.
(Item 28)
26. The crystalline form II according to any of items 23 to 25, wherein the crystal habit is plate-like.
(Item 29)
29. A method for making crystalline form II according to any of items 23 to 28, comprising using supercritical fluid (SCF) technology.
(Item 30)
29. A dosage form comprising a therapeutically neuroprotective amount of crystalline Form II according to any of items 23 to 28.
(Item 31)
29. A pharmaceutical composition for the treatment of Alzheimer's disease, comprising a therapeutically effective amount of crystalline form II according to any one of items 23 to 28.
(Item 32)
29. A method for treating Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of crystalline form II according to any of items 23 to 28.
(Item 33)
Crystalline Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride, characterized by the PXRD pattern shown in FIG.
(Item 34)
Crystalline Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride, characterized by the FTIR spectrum shown in FIG. 9. (Item 35)
Crystalline Form I of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride, characterized by the ¹ H-NMR spectrum shown in FIG.
II.
(Item 36)
36. The crystalline form III according to any of items 33 to 35, characterized by a particle shape as shown in FIG. 11.
(Item 37)
36. The crystalline form III according to any of items 33 to 35, characterized by a particle size as shown in FIG.
(Item 38)
36. The crystalline form III according to any one of items 33 to 35, wherein the crystal habit is lath-like.
(Item 39)
39. A method for making crystalline form III according to any of items 33 to 38, comprising using supercritical fluid (SCF) technology.
(Item 40)
39. A dosage form comprising a therapeutically neuroprotective amount of crystalline Form III according to any of items 33 to 38.
(Item 41)
39. A pharmaceutical composition for the treatment of Alzheimer's disease, comprising a therapeutically effective amount of crystalline Form III according to any one of items 33 to 38.
(Item 42)
39. A method for treating Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of crystalline Form III according to any of items 33 to 38.
(Item 43)
The metabolite ANAVEX19-144, characterized by the PXRD pattern shown in FIG.
(Item 44)
Metabolite ANAVEX19-144, characterized by DSC-TGA data shown in FIG.
(Item 45)
The metabolite ANAVEX19-144, characterized by the FTIR spectrum shown in FIG.
(Item 46)
46. The metabolite ANAVEX19-144 according to any of items 43 to 45, characterized by a particle shape as shown in FIG. 15.
(Item 47)
46. The metabolite ANAVEX19-144 according to any of items 43 to 45, characterized by a particle size as shown in FIG. 15.
(Item 48)
46. The metabolite ANAVEX19-144 according to any of items 43 to 45, wherein the crystal habit is needle-like.
(Item 49)
49. A method for producing the metabolite ANAVEX19-144 according to any one of items 43 to 48, which uses supercritical fluid (SCF) technology.
(Item 50)
49. A dosage form comprising a therapeutically neuroprotective amount of the metabolite ANAVEX 19-144 according to any one of items 43 to 48.
(Item 51)
A pharmaceutical composition for treating Alzheimer's disease, comprising a therapeutically effective amount of the metabolite ANAVEX19-144 according to any one of items 43 to 48.
(Item 52)
A method for treating Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of the metabolite ANAVEX19-144 according to any one of items 43 to 48.
(Item 53)
The metabolite ANAVEX19-144, characterized by the PXRD pattern shown in FIG.
(Item 54)
Metabolite ANAVEX19-144, characterized by DSC-TGA data shown in FIG.
(Item 55)
55. The metabolite ANAVEX19-144 according to any of items 53 to 54, characterized by a particle shape as shown in FIG. 16.
(Item 56)
55. The metabolite ANAVEX19-144 according to any of items 53 to 54, characterized by a particle size as shown in FIG. 16.
(Item 57)
57. A method for producing the metabolite ANAVEX19-144 according to any one of items 53 to 56, which uses supercritical fluid (SCF) technology.
(Item 58)
57. A dosage form comprising a therapeutically neuroprotective amount of the metabolite ANAVEX19-144 according to any one of items 53 to 56.
(Item 59)
57. A pharmaceutical composition for treating Alzheimer's disease, comprising a therapeutically effective amount of the metabolite ANAVEX19-144 according to any one of items 53 to 56.
(Item 60)
57. A method for treating Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of the metabolite ANAVEX19-144 according to any one of items 53 to 56.

FIG. 1 shows a powder X-ray diffraction (PXRD) pattern characteristic of polymorphic Form I of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);

FIG. 2 shows a scanning electron microscope (SEM) micrograph showing the particle size and morphology of polymorphic Form 1 of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) produced using acetonitrile as the solvent in a supercritical fluid process;

FIG. 3 shows SEM micrographs showing particle size and morphology of polymorphic Form 1 of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) produced using ethanol as a solvent in a supercritical fluid process;

FIG. 4 shows a PXRD pattern characteristic of polymorphic Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);

FIG. 5 shows a Fourier transform infrared spectroscopy (FTIR) spectrum characteristic of polymorphic Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);

FIG. 6 shows a proton nuclear magnetic resonance ( ¹ H-NMR) spectrum characteristic of polymorphic Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);

FIG. 7 shows SEM micrographs showing particle size and morphology of polymorphic Form II of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);

FIG. 8 shows a PXRD pattern characteristic of polymorphic Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);

FIG. 9 shows a FTIR spectrum characteristic of polymorphic Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);

FIG. 10 shows a ¹ H-NMR spectrum characteristic of polymorphic Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);

FIG. 11 shows a SEM micrograph showing the particle size and morphology of polymorphic Form III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73);

FIG. 12 shows a PXRD pattern characteristic of metabolite ANAVEX19-144 produced using ethanol as a solvent in a supercritical fluid process;

FIG. 13 shows DSC-TGA data characteristic of metabolite ANAVEX19-144 produced using ethanol as a solvent in a supercritical fluid process;

FIG. 14 shows a characteristic FTIR spectrum for metabolite ANAVEX19-144 produced using ethanol as a solvent in a supercritical fluid process;

FIG. 15 shows SEM micrographs showing particle size and morphology of metabolite ANAVEX19-144 produced using ethanol as a solvent in a supercritical fluid process;

FIG. 16 shows SEM micrographs showing particle size and morphology of metabolite ANAVEX19-144 produced using dichloromethane as a solvent in a supercritical fluid process;

FIG. 17 shows a PXRD pattern characteristic of metabolite ANAVEX19-144 produced using dichloromethane as a solvent in a supercritical fluid process; and

FIG. 18 shows DSC-TGA data characteristic of metabolite ANAVEX19-144 produced using dichloromethane as the solvent in a supercritical fluid process.

DETAILED DESCRIPTION Various embodiments of the present disclosure are discussed in detail below. While specific implementations are discussed, it should be understood that this is done for illustrative purposes only. A person skilled in the relevant art will recognize that other components and configurations can be used without departing from the spirit and scope of the present disclosure.

First, illustrative implementations of one or more embodiments are illustrated below, but it should be understood that the disclosed methods may be implemented using any number of techniques. The present disclosure should in no way be limited to the illustrative implementations, drawings, and techniques illustrated herein, but may be modified within the scope of the appended claims, along with their full range of equivalents.

In the following discussion and in the claims, the terms "including" and "comprising" are used in an open manner and are therefore to be construed to mean "including, but not limited to." The various features described in more detail below will be readily apparent to those skilled in the art with the aid of this disclosure upon reading the following detailed description and upon reference to the accompanying drawings.

The present disclosure relates to tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (also referred to as ANAVEX 2-73):

ANAVEX2-73 has been reported to exhibit neuroprotective potential against amyloid toxicity in mice. In particular, ANAVEX2-73 was reported to reduce oxidative stress, caspase induction, cell loss, and learning and memory impairment observed in mice one week after i.c.v. injection of an oligomeric preparation of amyloid beta _25-35 peptide (Aβ _25-35 ). See J. Psychopharmacol. 25(8), 1101-1117 (2011). More recently, it was reported that ANAVEX2-73 blocked Aβ _25-35 -induced P-Akt decrease and P-GSK-3β increase, indicating activation in the PI3K neuroprotective pathway. See Neuropsychopharmacology 38, 1706-1723 (2013). At the dose range tested, ANAVEX2-73 reduced hyperphosphorylation of Tau on physiological epitopes (AT-8 antibody clone) and pathological epitopes (AT-100 clone). ANAVEX2-73 was also reported to reduce Aβ _25-35 induced endogenous Aβ _1-42 seeding.

U.S. Patent Publication No. 2014/0296211 (entitled "ANAVEX2-73 AND CERTAIN ANTICHOLINESTERASE INHIBITORS COMPOSITION AND METHOD FOR NEUROPROTECTION," Vamvakides et al., filed July 12, 2013); U.S. Patent No. 62/065,833 (entitled "A19-144, A2-73 AND CERTAIN ANTICHOLINESTERASE INHIBITOR COMPOSITIONS AND METHOD FOR NEUROPROTECTION");
Reference is made to U.S. Patent Publication No. 2014/0133631, entitled "METHOD FOR ANTI-SEIZURE THERAPY," filed October 20, 2014; U.S. Patent Publication No. 2014/0133631, entitled "ANAVEX2-73 FOR THE TREATMENT OF ALZHEIMER'S DISEASE," filed on the same date; and U.S. Patent Publication No. 2014/0133631, entitled "ENANTIOMERS OF A2-73, ANALOGUES, AND SIGMA AGONIST ACTIVITY," filed on the same date. The teachings of these applications and publications, and all references cited herein, are incorporated by reference in their entirety.

The present disclosure provides a crystalline polymorph of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (Form I) characterized by the PXRD and other data provided herein.

The present disclosure provides another crystalline polymorph (Form II) of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride, characterized by the PXRD and other data provided herein.

The present disclosure further provides another crystalline polymorph (Form III) of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride characterized by the PXRD and other data provided herein.

The present disclosure also provides a metabolite of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (also referred to as ANAVEX 19-144), characterized by the PXRD and other data provided herein, and having the following structure:

The present disclosure further provides for the use of the polymorphs and metabolite substances in the treatment of Alzheimer's disease.

Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) was characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance ( ¹ H-NMR) and scanning electron microscopy (SEM), as detailed in Figures 1-15.

The present disclosure further provides a process for preparing polymorphic forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73). In one embodiment, the polymorphic forms (disclosed herein) may be prepared by a supercritical fluid (SCF) anti-solvent process. In one embodiment, the anti-solvent is a supercritical fluid, although in some embodiments, a near-critical fluid may also be suitable. A "supercritical fluid" is a fluid when it is simultaneously at or above its critical pressure (Pc) and critical temperature (Tc). In practice, the pressure of the fluid will likely range between 1.01 and 7.0 times its critical pressure, and the temperature will range between 1.01 and 4.0 times its critical temperature (in Kelvin). However, some fluids (e.g., helium and neon) have particularly low critical pressures and temperatures (by a factor of 10) and may need to be used under operating conditions that are in large excess of their critical values (e.g., up to 200 times the relevant critical values). The term "near-critical fluid" encompasses both high pressure liquids (which are fluids at or above their critical pressures, but below (but preferably near) their critical temperatures) and high density vapors (which are fluids at or above their critical 15 temperatures, but below (but preferably near) their critical pressures). By way of example, a high pressure liquid may have a pressure between about 1.01 and 7 times its Pc and a temperature between about 0.5 and 0.99 times its Tc. A high density vapor may correspondingly have a pressure between about 0.5 and 0.99 times its Pc and a temperature between about 1.01 and 4 times its Tc.

Suitably, the anti-solvent and the solution may be introduced into the precipitation chamber via respective paths each having an outlet, the outlets being arranged relative to each other such that the anti-solvent introduced through the first path and the solution introduced through the second path both enter the precipitation chamber at substantially the same point, which is substantially the point where the anti-solvent and the solution meet. To provide a good level of mixing and dispersion, the anti-solvent and the solution may be co-fed into the precipitation chamber, for example, via nozzles having coaxial paths terminating adjacent each other. Alternatively, one or more streams of the anti-solvent may be arranged to impinge on a stream of the solution to provide a good level of mixing and dispersion. However, other mixing configurations are also possible. Examples of suitable devices are known, inter alia, from WO-30 95/01221, WO-96/00610, WO-98/36825, WO-99/44733, WO-99/59710, WO-01/03821, and WO-03/008082, which are incorporated herein by reference.

According to the present disclosure, new crystalline forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) were prepared by a supercritical fluid (SCF) process. The basic process involved preparing a solution of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) in a suitable solvent (e.g., acetonitrile or ethanol) and introducing the solution into an SCF environment (typically supercritical CO ₂ ) in a pressure vessel. The supercritical CO ₂ acted as a strong anti-solvent, allowing for rapid precipitation of the particles. Different polymorphic forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) were produced by manipulating the SCF process parameters, including the solvent used, flow rate, pressure, and temperature. Furthermore, manipulation of the SCF process parameters determined the size, morphology, and crystal habit of the crystalline particles produced by the SCF process.

The SCF process parameters used to produce the three polymorphic forms I-III of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) are provided in Tables 1-3. As shown in Table 1, crystalline Form I was produced by placing the ANAVEX2-73 starting material in acetonitrile or ethanol solvents and processed by supercritical fluid technology. The resulting particle shape was different depending on the solvent. The particle shape of crystalline Form I produced using acetonitrile solvent was plate-like. As used herein, the term "plate-like" refers to flat particles of similar length and width. The particle shape of crystalline Form I produced using ethanol solvent was conglomerate. As used herein, the term "conglomerate" refers to a mixture of two or more types of particle shapes. The resulting material was characterized by PXRD and SEM. The PXRD of crystalline form I of ANAVEX2-73 is shown in Figure 1. SEM micrographs showing the particle size and morphology of crystalline form I are shown in Figures 2-3. Figure 2 shows the particle size and morphology of crystalline form I produced using acetonitrile solvent (plate morphology). Figure 3 shows the particle size and morphology of crystalline form I produced using ethanol as the solvent (conglomerate morphology).

As shown in Table 2, crystalline Form II was produced by placing the ANAVEX2-73 starting material in a solvent of acetonitrile, 1:9 v/v trifluoroethanol+ethanol, 1:1 v/v acetone+ethanol, or 3-methyl-1-butanol and processed by supercritical fluid technology. In all cases, crystalline Form II was characterized by a plate-like crystal habit. The resulting material was characterized by PXRD and SEM. The PXRD of crystalline Form II of ANAVEX2-73 is shown in FIG. 4. Crystalline Form II is further characterized by the FTIR spectrum shown in FIG. 5 and ^{the 1} H-NMR spectrum shown in FIG. 6. A SEM micrograph showing the particle size and morphology of crystalline Form II is shown in FIG. 7.

As shown in Table 3, crystalline Form III was produced by placing the ANAVEX2-73 starting material in a solvent of ethanol or 1:9 v/v trifluoroethanol+ethanol and processed by supercritical fluid technology. In all cases, crystalline Form III was characterized by a lath-like crystal habit. As used herein, "lath-like" refers to long, thin, blade-like particles. The resulting material was characterized by PXRD and SEM. The PXRD of crystalline Form III of ANAVEX2-73 is shown in FIG. 8. Crystalline Form III is further characterized by the FTIR spectrum shown in FIG. 9 and ^{the 1} H-NMR spectrum shown in FIG. 10. A SEM micrograph showing the particle size and morphology of crystalline Form III is shown in FIG. 11.

The present disclosure also provides ANAVEX 19-144, a metabolite of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride. ANAVEX 19-144 has demonstrated similar antiamnesic and neuroprotective potential to ANAVEX 2-73. See, e.g., J. of Psychopharmacol. 25(8),
1101-1117 (2011). Crystalline forms of ANAVEX19-144 were produced by placing the ANAVEX19-144 starting material in a solvent of ethanol or dichloromethane and processed by supercritical fluid technology. The crystal forms of ANAVEX19-144 produced by supercritical fluid technology under process parameters of 40 mg/mL ethanol solution, pressure 200 bar, temperature 80° C., supercritical _CO2 solution with flow rate of 20 g/min and TS flow 0.4 mL/min were characterized by PXRD, FTIR, DSC, and SEM as shown in Figures 12-15. As shown in Figure 15, the crystal forms of ANAVEX19-144 were characterized by needle-like crystals. In contrast, the crystalline form of ANAVEX 19-144 produced by similar process parameters using the solvent dichloromethane exhibited a mixed crystal habit of needle-like and lath-type particles, as shown in Figure 16. The crystalline form of ANAVEX 19-144 produced using the dichloromethane supercritical fluid technique yielded a powder with better flow characteristics and improved flow properties for downstream processing. The crystalline form of ANAVEX 19-144 was further characterized by PXRD and DSC, as shown in Figures 17-18. The two crystalline forms of ANAVEX 19-144 (produced according to the supercritical fluid technique in ethanol or dichloromethane) were stored in uncovered containers for one week at 40°C in 75% relative humidity and then characterized by PXRD to determine the stability of the two forms. After one week, PXRD of the two forms did not show any differences, thus indicating that the two forms were stable under the conditions tested.

Claims (10)

A crystal of ANAVEX19-144, wherein ANAVEX19-144 is

wherein the crystal has a PXRD pattern including peaks having 2θ values of 4.26, 6.68, 7.46, 7.98, 8.65, 9.15, 13.49, 14.61, 16.48, 18.77, 20.41, 21.84, 22.63, 23.32, and 27.87. A crystal of ANAVEX19-144, wherein ANAVEX19-144 is

wherein the crystal has a PXRD pattern including peaks having 2θ values of 4.10, 4.90, 7.87, 8.94, 9.64, 11.27, 12.87, 14.06, 15.11, 15.61, 15.88, 17.03, 19.16, 19.75, 20.77, 21.77, 22.36, 23.20, 23.81, 25.17, 27.51, and 28.15. 10. The crystal of claim 1, wherein the crystal is further characterized by an acicular habit. 3. The crystal of claim 2, wherein the crystal is further characterized by a mixed crystal habit of needle-like and lath-type particles. A pharmaceutical composition having a form for administration, comprising a therapeutically neuroprotective amount of the crystal according to any one of claims 1 to 4. A pharmaceutical composition for use in treating Alzheimer's disease, comprising a therapeutically effective amount of the crystal of any one of claims 1 to 4. Use of the crystal according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of Alzheimer's disease. 1. A method of making crystals of ANAVEX 19-144, comprising the steps of crystallizing said ANAVEX 19-144 in a supercritical fluid (SCF) environment;
the SCF comprises supercritical carbon dioxide, and
The SCF environment comprises a supercritical carbon dioxide solution having a pressure of 200 bar, a temperature of 80° C., a flow rate of 20 g/min, and a TS flow of 0.4 mL/min;
Method. 9. The method of claim 8, wherein the crystallizing step comprises:
a. making a solution of ANAVEX 19-144 in a solvent, the solvent comprising ethanol or dichloromethane;
b. introducing the solution into the SCF;
c. crystallizing ANAVEX 19-144 in said SCF environment to form crystals;
d. Obtaining the crystals of ANAVEX19-144 by isolating the crystals.
The method includes: The method according to claim 9, wherein the obtained crystals of ANAVEX19-144 are the crystals according to claim 1 when the solvent is ethanol, and are the crystals according to claim 2 when the solvent is dichloromethane.

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